Theoretical studies on the binding of rhenium(I) complexes to inducible nitric oxide synthase

• Type: Article in International Scientific Journal
• Date: 2013

Authors

Bruno L Oliveira (Author) Other; Irina S Moreira (Author) Other; Pedro A Fernandes (Author) FCUP; Maria J Ramos (Author) FCUP; Isabel Santos (Author) Other; Joao D G Correia (Author) Other

Journal

Title: Journal of Molecular Graphics and Modelling

Vol. 45

Pages: 13-25

ISSN: 1093-3263

Publisher: Elsevier

Indexing

ISI Web of Knowledge - 13 Citations

Scopus - 12 Citations

Scientific classification

FOS: Natural sciences > Computer and information sciences

Other information

Authenticus ID: P-008-EC4

DOI: 10.1016/j.jmgm.2013.07.007

Abstract (EN): Considering our interest in the design of innovative radiometal-based complexes for in vivo imaging of nitric oxide synthase (NOS), we have recently introduced a set of M(CO)(3)-complexes (M=Tc-99m, Re) containing a pendant N-omega-NO2-L-arginine moiety, a known inhibitor of the enzyme. Enzymatic assays with purified inducible NOS have shown that the non-radioactive surrogates with 3-(Re1; K-i=84 mu M) or 6-carbon linkers (Re2; K-i=6 mu M) are stronger inhibitors than the respective metal-free conjugates Li (K-i=178 mu M) and 12 (K-i=36 mu M), with Re2 displaying the highest inhibitory potency. Aiming to rationalize the experimental results we have performed a molecular docking study combined with molecular dynamics (MD) simulations and free energy perturbation (FEP) calculations. The higher inhibitory potency of Re2 arises from the stronger electrostatic interactions observed between the "Re(CO)(3)" core and the residues Arg260 and Arg382. This interaction is only possible due to the higher flexibility of its C6-carbon spacer, which links the N-omega-NO2-L-arginine moiety and the "Re(CO)(3)" organometallic core. Furthermore, FEP calculations were carried out and the resultant relative binding energies (Delta Delta G(bind)(calc)=0.690 +/- 0.028 kcal/mol, Re1/L1 and 1.825 +/- 0.318 kcal/mol, Re2/L2) are in accordance with the experimental results (Delta Delta G(bind)(calc)=0.461 +/- 0.009 kcal/mol, Re1/L1 and 1.129 +/- 0.210 kcal/mol, Re2/L2); there is an energetic penalty for the transformation of the Re complexes into the ligands and this penalization is higher for the pair Re2/12.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 13